IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis

Autoři: Deepak Tripathi aff001;  Rajesh Kumar Radhakrishnan aff001;  Ramya Sivangala Thandi aff001;  Padmaja Paidipally aff001;  Kamakshi Prudhula Devalraju aff002;  Venkata Sanjeev Kumar Neela aff002;  Madeline Kay McAllister aff001;  Buka Samten aff001;  Vijaya Lakshmi Valluri aff002;  Ramakrishna Vankayalapati aff001
Působiště autorů: Department of Pulmonary Immunology, Center for Biomedical Research, The University of Texas Health Center, Tyler, Texas, TX, United States of America aff001;  Immunology and Molecular Biology Department, Bhagwan Mahavir Medical Research Centre, Hyderabad, Telangana, India aff002
Vyšlo v časopise: IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis. PLoS Pathog 15(12): e1008140. doi:10.1371/journal.ppat.1008140
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1008140


Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.

Klíčová slova:

Body weight – Tuberculosis – Inflammation – Flow cytometry – Epithelial cells – Adoptive transfer


1. Kumar NP, Sridhar R, Banurekha VV, Jawahar MS, Fay MP, Nutman TB, et al. Type 2 diabetes mellitus coincident with pulmonary tuberculosis is associated with heightened systemic type 1, type 17, and other proinflammatory cytokines. Ann Am Thorac Soc. 2013;10: 441–449. doi: 10.1513/AnnalsATS.201305-112OC 23987505

2. Ronacher K, Joosten SA, van Crevel R, Dockrell HM, Walzl G, Ottenhoff THM. Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus. Immunol Rev. 2015;264: 121–137. doi: 10.1111/imr.12257 25703556

3. Lachmandas E, van den Heuvel CNAM, Damen MSMA, Cleophas MCP, Netea MG, van Crevel R. Diabetes Mellitus and Increased Tuberculosis Susceptibility: The Role of Short-Chain Fatty Acids. J Diabetes Res. 2016;2016. doi: 10.1155/2016/6014631 27057552

4. Kumar Nathella P, Babu S. Influence of diabetes mellitus on immunity to human tuberculosis. Immunology. 2017;152: 13–24. doi: 10.1111/imm.12762 28543817

5. Cernea S, Dobreanu M. Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. Biochem Med (Zagreb). 2013;23: 266–280. doi: 10.11613/BM.2013.033 24266296

6. Chng MHY, Alonso MN, Barnes SE, Nguyen KD, Engleman EG. Adaptive Immunity and Antigen-Specific Activation in Obesity-Associated Insulin Resistance. Mediators Inflamm. 2015;2015. doi: 10.1155/2015/593075 26146464

7. Martinez N, Kornfeld H. Diabetes and immunity to tuberculosis. Eur J Immunol. 2014;44: 617–626. doi: 10.1002/eji.201344301 24448841

8. Lee M-R, Huang Y-P, Kuo Y-T, Luo C-H, Shih Y-J, Shu C-C, et al. Diabetes Mellitus and Latent Tuberculosis Infection: A Systemic Review and Metaanalysis. Clin Infect Dis. 2017;64: 719–727. doi: 10.1093/cid/ciw836 27986673

9. Dooley KE, Tang T, Golub JE, Dorman SE, Cronin W. Impact of Diabetes Mellitus on Treatment Outcomes of Patients with Active Tuberculosis. Am J Trop Med Hyg. 2009;80: 634–639. 19346391

10. Restrepo BI. Diabetes and tuberculosis. Microbiol Spectr. 2016;4. doi: 10.1128/microbiolspec.TNMI7-0023-2016 28084206

11. Zheng H, Wu J, Jin Z, Yan L-J. Potential Biochemical Mechanisms of Lung Injury in Diabetes. Aging Dis. 2017;8: 7–16. doi: 10.14336/AD.2016.0627 28203478

12. Mayer-Barber KD, Barber DL. Innate and Adaptive Cellular Immune Responses to Mycobacterium tuberculosis Infection. Cold Spring Harb Perspect Med. 2015;5. doi: 10.1101/cshperspect.a018424 26187873

13. Vallerskog T, Martens GW, Kornfeld H. Diabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis. J Immunol. 2010;184: 6275–6282. doi: 10.4049/jimmunol.1000304 20421645

14. Domingo-Gonzalez R, Prince O, Cooper A, Khader S. Cytokines and Chemokines in Mycobacterium tuberculosis infection. Microbiol Spectr. 2016;4. doi: 10.1128/microbiolspec.TBTB2-0018-2016 27763255

15. Sampath P, Moideen K, Ranganathan UD, Bethunaickan R. Monocyte Subsets: Phenotypes and Function in Tuberculosis Infection. Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.00009

16. Stew SS, Martinez PJ, Schlesinger LS, Restrepo BI. Differential expression of monocyte surface markers among TB patients with diabetes co-morbidity. Tuberculosis (Edinb). 2013;93: S78–S82. doi: 10.1016/S1472-9792(13)70015-5 24388654

17. Wang CH, Yu CT, Lin HC, Liu CY, Kuo HP. Hypodense alveolar macrophages in patients with diabetes mellitus and active pulmonary tuberculosis. Tuber Lung Dis. 1999;79: 235–242. doi: 10.1054/tuld.1998.0167 10692992

18. Kumar NP, Moideen K, Viswanathan V, Sivakumar S, Menon PA, Kornfeld H, et al. Heightened circulating levels of antimicrobial peptides in tuberculosis—Diabetes co-morbidity and reversal upon treatment. PLoS One. 2017;12. doi: 10.1371/journal.pone.0184753 28910369

19. Cheekatla SS, Tripathi D, Venkatasubramanian S, Nathella PK, Paidipally P, Ishibashi M, et al. NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection. PLoS Pathog. 2016;12: e1005972. doi: 10.1371/journal.ppat.1005972 27783671

20. Eberl G, Colonna M, Di Santo JP, McKenzie ANJ. Innate Lymphoid Cells: a new paradigm in immunology. Science. 2015;348: aaa6566. doi: 10.1126/science.aaa6566 25999512

21. Vivier E, van de Pavert SA, Cooper MD, Belz GT. The evolution of innate lymphoid cells. Nat Immunol. 2016;17: 790–794. doi: 10.1038/ni.3459 27328009

22. Ebbo M, Crinier A, Vély F, Vivier E. Innate lymphoid cells: major players in inflammatory diseases. Nature Reviews Immunology. 2017;17: 665–678. doi: 10.1038/nri.2017.86 28804130

23. Bando JK, Colonna M. Innate lymphoid cell function in the context of adaptive immunity. Nat Immunol. 2016;17: 783–789. doi: 10.1038/ni.3484 27328008

24. Ardain A, Domingo-Gonzalez R, Das S, Kazer SW, Howard NC, Singh A, et al. Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis. Nature. 2019;570: 528–532. doi: 10.1038/s41586-019-1276-2 31168092

25. Dhiman R, Indramohan M, Barnes PF, Nayak RC, Paidipally P, Rao LVM, et al. IL-22 produced by human NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion. J Immunol. 2009;183: 6639–6645. doi: 10.4049/jimmunol.0902587 19864591

26. Ronacher K, Sinha R, Cestari M. IL-22: An Underestimated Player in Natural Resistance to Tuberculosis? Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.00009

27. Treerat P, Prince O, Cruz-Lagunas A, Muñoz-Torrico M, Salazar-Lezama MA, Selman M, et al. Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection. Mucosal Immunol. 2017;10: 1069–1081. doi: 10.1038/mi.2017.15 28247861

28. Dhiman R, Periasamy S, Barnes PF, Jaiswal AG, Paidipally P, Barnes AB, et al. NK1. 1+ cells and IL-22 regulate vaccine-induced protective immunity against challenge with Mycobacterium tuberculosis. The Journal of Immunology. 2012;189: 897–905. doi: 10.4049/jimmunol.1102833 22711885

29. Yi P, Liang Y, Yuan DMK, Jie Z, Kwota Z, Chen Y, et al. A tightly regulated IL-22 response maintains immune functions and homeostasis in systemic viral infection. Scientific Reports. 2017;7: 3857. doi: 10.1038/s41598-017-04260-0 28634408

30. Gimeno Brias S, Stack G, Stacey MA, Redwood AJ, Humphreys IR. The Role of IL-22 in Viral Infections: Paradigms and Paradoxes. Front Immunol. 2016;7. doi: 10.3389/fimmu.2016.00007

31. Alabbas SY, Begun J, Florin TH, Oancea I. The role of IL‐22 in the resolution of sterile and nonsterile inflammation. Clin Transl Immunology. 2018;7. doi: 10.1002/cti2.1017 29713472

32. Zenewicz LA, Flavell RA. Recent advances in IL-22 biology. Int Immunol. 2011;23: 159–163. doi: 10.1093/intimm/dxr001 21393631

33. Sonnenberg GF, Fouser LA, Artis D. Functional biology of the IL-22-IL-22R pathway in regulating immunity and inflammation at barrier surfaces. Adv Immunol. 2010;107: 1–29. doi: 10.1016/B978-0-12-381300-8.00001-0 21034969

34. Kumar NP, Banurekha VV, Nair D, Kumaran P, Dolla CK, Babu S. Type 2 diabetes—tuberculosis co-morbidity is associated with diminished circulating levels of IL-20 subfamily of cytokines. Tuberculosis (Edinb). 2015;95: 707–712. doi: 10.1016/ 26354610

35. Ronacher K, van Crevel R, Critchley JA, Bremer AA, Schlesinger LS, Kapur A, et al. Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 2: Underlying Biologic Mechanisms. Chest. 2017;152: 174–180. doi: 10.1016/j.chest.2017.02.032 28434937

36. Wang X, Ota N, Manzanillo P, Kates L, Zavala-Solorio J, Eidenschenk C, et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature. 2014;514: 237–241. doi: 10.1038/nature13564 25119041

37. Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med. 2014;20: 1417–1426. doi: 10.1038/nm.3705 25362253

38. Woting A, Blaut M. Small Intestinal Permeability and Gut-Transit Time Determined with Low and High Molecular Weight Fluorescein Isothiocyanate-Dextrans in C3H Mice. Nutrients. 2018;10. doi: 10.3390/nu10060685 29843428

39. Venkatasubramanian S, Tripathi D, Tucker T, Paidipally P, Cheekatla S, Welch E, et al. Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection. Eur J Immunol. 2015. doi: 10.1002/eji.201545817 26471500

40. Fukaya T, Fukui T, Uto T, Takagi H, Nasu J, Miyanaga N, et al. Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation. Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.00009

41. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9: 7204–7218. doi: 10.18632/oncotarget.23208 29467962

42. Rock KL, Kono H. The inflammatory response to cell death. Annu Rev Pathol. 2008;3: 99–126. doi: 10.1146/annurev.pathmechdis.3.121806.151456 18039143

43. Robb CT, Regan KH, Dorward DA, Rossi AG. Key mechanisms governing resolution of lung inflammation. Semin Immunopathol. 2016;38: 425–448. doi: 10.1007/s00281-016-0560-6 27116944

44. McDonough KA, Kress Y. Cytotoxicity for lung epithelial cells is a virulence-associated phenotype of Mycobacterium tuberculosis. Infect Immun. 1995;63: 4802–4811. 7591139

45. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil Function: From Mechanisms to Disease. Annual Review of Immunology. 2012;30: 459–489. doi: 10.1146/annurev-immunol-020711-074942 22224774

46. König J, Wells J, Cani PD, García-Ródenas CL, MacDonald T, Mercenier A, et al. Human Intestinal Barrier Function in Health and Disease. Clin Transl Gastroenterol. 2016;7: e196. doi: 10.1038/ctg.2016.54 27763627

47. de Kort S, Keszthelyi D, Masclee A a. M. Leaky gut and diabetes mellitus: what is the link? Obes Rev. 2011;12: 449–458. doi: 10.1111/j.1467-789X.2010.00845.x 21382153

48. Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes. 2017;8: 249–269. doi: 10.4239/wjd.v8.i6.249 28694926

49. Valeri M, Raffatellu M. Cytokines IL-17 and IL-22 in the host response to infection. Pathog Dis. 2016;74. doi: 10.1093/femspd/ftw111 27915228

50. Lo BC, Shin SB, Hernaez DC, Refaeli I, Yu HB, Goebeler V, et al. IL-22 Preserves Gut Epithelial Integrity and Promotes Disease Remission during Chronic Salmonella Infection. The Journal of Immunology. 2019; ji1801308. doi: 10.4049/jimmunol.1801308 30617224

51. Zheng C, Hu M, Gao F. Diabetes and pulmonary tuberculosis: a global overview with special focus on the situation in Asian countries with high TB-DM burden. Glob Health Action. 2017;10. doi: 10.1080/16549716.2016.1264702 28245710

52. Berkowitz N, Okorie A, Goliath R, Levitt N, Wilkinson RJ, Oni T. The prevalence and determinants of active tuberculosis among diabetes patients in Cape Town, South Africa, a high HIV/TB burden setting. Diabetes Res Clin Pract. 2018;138: 16–25. doi: 10.1016/j.diabres.2018.01.018 29382589

53. Leegaard A, Riis A, Kornum JB, Prahl JB, Thomsen VØ, Sørensen HT, et al. Diabetes, Glycemic Control, and Risk of Tuberculosis: A population-based case-control study. Diabetes Care. 2011;34: 2530–2535. doi: 10.2337/dc11-0902 21972407

54. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009;9: 737–746. doi: 10.1016/S1473-3099(09)70282-8 19926034

55. Kumar NP, Nair D, Banurekha VV, Chandrakumar D, Kumaran P, Sridhar R, et al. Type 2 diabetes mellitus coincident with pulmonary or latent tuberculosis results in modulation of adipocytokines. Cytokine. 2016;79: 74–81. doi: 10.1016/j.cyto.2015.12.026 26771473

56. Dudakov JA, Hanash AM, van den Brink MRM. Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 2015;33: 747–785. doi: 10.1146/annurev-immunol-032414-112123 25706098

57. Bayes HK, Ritchie ND, Ward C, Corris PA, Brodlie M, Evans TJ. IL-22 exacerbates weight loss in a murine model of chronic pulmonary Pseudomonas aeruginosa infection. J Cyst Fibros. 2016;15: 759–768. doi: 10.1016/j.jcf.2016.06.008 27375092

58. Felton JM, Duffin R, Robb CT, Crittenden S, Anderton SM, Howie SEM, et al. Facilitation of IL-22 production from innate lymphoid cells by prostaglandin E2 prevents experimental lung neutrophilic inflammation. Thorax. 2018;73: 1081–1084. doi: 10.1136/thoraxjnl-2017-211097 29574419

59. Ivanov S, Renneson J, Fontaine J, Barthelemy A, Paget C, Fernandez EM, et al. Interleukin-22 Reduces Lung Inflammation during Influenza A Virus Infection and Protects against Secondary Bacterial Infection. Journal of Virology. 2013;87: 6911–6924. doi: 10.1128/JVI.02943-12 23596287

60. Andrews C, McLean MH, Durum SK. Cytokine Tuning of Intestinal Epithelial Function. Front Immunol. 2018;9. doi: 10.3389/fimmu.2018.00009

61. Rendon JL, Li X, Akhtar S, Choudhry MA. IL-22 modulates gut epithelial and immune barrier functions following acute alcohol exposure and burn injury. Shock. 2013;39: 11–18. doi: 10.1097/SHK.0b013e3182749f96 23143063

62. Lanfranca MP, Lin Y, Fang J, Zou W, Frankel T. Biological and Pathological Activities of Interleukin-22. J Mol Med (Berl). 2016;94: 523–534. doi: 10.1007/s00109-016-1391-6 26923718

63. Guillon A, Jouan Y, Brea D, Gueugnon F, Dalloneau E, Baranek T, et al. Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence. European Respiratory Journal. 2015;46: 771–782. doi: 10.1183/09031936.00215114 26250498

64. Li Z, Hodgkinson T, Gothard EJ, Boroumand S, Lamb R, Cummins I, et al. Epidermal Notch1 recruits RORγ+ group 3 innate lymphoid cells to orchestrate normal skin repair. Nature Communications. 2016;7: 11394. doi: 10.1038/ncomms11394 27099134

65. Cella M, Miller H, Song C. Beyond NK Cells: The Expanding Universe of Innate Lymphoid Cells. Front Immunol. 2014;5. doi: 10.3389/fimmu.2014.00005

66. Wang S, Xia P, Chen Y, Qu Y, Xiong Z, Ye B, et al. Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation. Cell. 2017;171: 201–216.e18. doi: 10.1016/j.cell.2017.07.027 28844693

67. Ouyang W, O’Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019;50: 871–891. doi: 10.1016/j.immuni.2019.03.020 30995504

68. Mühl H, Scheiermann P, Bachmann M, Härdle L, Heinrichs A, Pfeilschifter J. IL-22 in tissue-protective therapy. Br J Pharmacol. 2013;169: 761–771. doi: 10.1111/bph.12196 23530726

69. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C. Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease. Cellular and Molecular Gastroenterology and Hepatology. 2017;4: 33–46. doi: 10.1016/j.jcmgh.2017.03.007 28560287

70. Armstrong LE, Lee EC, Armstrong EM. Interactions of Gut Microbiota, Endotoxemia, Immune Function, and Diet in Exertional Heatstroke. In: Journal of Sports Medicine [Internet]. 2018 [cited 28 Mar 2019]. doi: 10.1155/2018/5724575 29850597

Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens

2019 Číslo 12

Najčítanejšie v tomto čísle

Tejto téme sa ďalej venujú…

Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.


Nemáte účet?  Registrujte sa